Although there are advancements in the field of breast cancer screening, diagnosis, and treatment, about 12% of these patients globally eventually develop metastatic breast cancer; the 5-year survival rate of metastatic breast cancer is just 26%.1 A plethora of newer approved treatment regimens are available for treating metastatic breast cancers ranging from newer chemotherapies to hormonal therapies and immunotherapies. However, the success stories of these therapies are highly variable in different subsets of patient populations. This may be due to presence or absence of specific genes or gene sequences (referred as biomarkers) in these patients. 

With advances in genomics and with the advent of more advanced next generation sequencing (NGS) and comprehensive genomic profiling techniques, it is possible to individualize treatment, i.e. identify the right candidate for the right treatment. Several studies in metastatic breast cancer have proved how these prognostic and predictive biomarkers have helped the clinicians to take appropriate therapeutic decision with minimal toxicity to their patients.

While estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are amongst the first biomarkers to be studied and implemented in clinical studies, there are many more tissue based and circulating biomarkers already available and several more in pipeline, being tested. There is thus an unmet need to understand the utility of these biomarkers in clinical practice. 

In view of this, ASCO, in the recently published updated guidelines, provides a detailed biomarker-based approach in systemic therapy decisions in metastatic breast cancer. These updated recommendations to the 2015 ASCO guidelines were developed by a multidisciplinary expert panel using systematic review of published literature. The recommendations include only those biomarker assays which were evaluated by FDA during drug approval process. The biomarkers recommended and not recommended by ASCO are mentioned in fig.1.2 The ASCO recommendations include:

        Fig. 1

• Patients with locally recurrent unresectable or metastatic HR+ HER2- breast cancer should be tested for PIK3CA mutations using NGS or circulating DNA (ctDNA) before initiating treatment with PIK3CA inhibitor and hormonal therapy (eg- alpelisib plus fulvestrant). Patients negative for PIK3CA mutation using tissue sample should also be checked using ctDNA.
• Although there are studies suggesting aromatase inhibitors are not efficacious than fulvestrant in patient with ESR1 mutation, there is insufficient information to suggest for ESR1 mutation testing in HR+, HER2- breast cancers.
• Patients should be tested for germline BRCA1 and BRCA2 mutations to determine if they are eligible to receive PARP inhibitor therapies.
• There is little knowledge available to suggest if germline PALB2- pathogenic variant can be used to decide if the patient with metastatic breast cancer is eligible to receive PARP inhibitor therapies.
• Little is known if testing for homologous recombination deficiency can help clinicians with therapeutic decisions.
• Patients who are candidates for immune checkpoint inhibitor (ICI) therapy should be tested for programmed cell death ligand-1 (PD L-1) before initiating therapy 
• Patients should also be tested for deficient mismatch repair or high microsatellite instability before assigning ICI therapy especially dostarlimab-gxly or pembrolizumab.
• Tumor mutational burden should be tested in patients before initiating pembrolizumab monotherapy.
• NTRK fusion tests may be asked before initiating a TRK inhibitor like larotrectinib or entrectinib.
• Not much information is available to suggest if TROP2- expression testing can help deciding a therapy involving anti-TROP2 antibody drug conjugate in HR-, HER2- metastatic breast cancer.
• Similarly, there is very limited evidence to recommend ctDNA testing or use of circulating tumor cells for response monitoring in metastatic breast cancer.2

References:

• O Peart. Metastatic breast cancer. Radiol Technol. 2017;88(5):519M-539M.
• L Henry et al. Biomarkers for systemic therapy in metastatic breast cancer: ASCO guideline update. J Clin Oncol. 2022.